Undetectable MRD Status in Patients with R/R CLL/SLL with Stable Disease after Lisocabtagene Maraleucel Treatment: Exploratory Analysis of the TRANSCEND CLL 004 Study

Background: For patients (pts) with R/R CLL/SLL after failure of Bruton tyrosine kinase inhibitor (BTKi) and B-cell lymphoma 2 inhibitor (BCL2i)–based treatment, there is no established standard of care and therefore there is a high unmet therapeutic need. The phase 1/2 TRANSCEND CLL 004 study (NCT03331198) investigated the efficacy and safety of lisocabtagene maraleucel (liso-cel) monotherapy, an autologous CD19-directed CAR T cell therapy, in pts with heavily pretreated R/R CLL/SLL and ≥ 2 previous lines of therapy, including a BTKi. The primary analysis demonstrated durable CR/CR with incomplete marrow recovery (CRi) per 2018 International Workshop on CLL (iwCLL 2018) criteria, high undetectable MRD (uMRD; 10⁻⁴ sensitivity) rates, and a manageable safety profile in pts who received liso-cel (Siddiqi T, et al. Lancet 2023). All evaluable responders (CR/CRi/PR) achieved blood uMRD status. Among evaluable pts with stable disease (SD), uMRD status was associated with longer median PFS (6.4 months) versus MRD-positive (MRD+) status (PFS, 2.8 months). This exploratory analysis aimed to better understand potential variables associated with achieving uMRD in pts who had SD with liso-cel.

Methods: Among 96 pts in the full efficacy set who were treated with liso-cel at dose level 1 (50 × 10⁶ CAR⁺ T cells) or 2 (100 × 10⁶ CAR⁺ T cells), 80 pts were evaluable for peripheral blood MRD. Peripheral blood MRD status was assessed by next-generation sequencing (NGS; clonoSEQ) assay; uMRD was defined as < 10⁻⁴ (< 1 CLL cell per 10,000) at 1 or more postinfusion time points. Additional exploratory analysis leveraged sample-level MRD results defined by total clonal cells/total nucleated cells assessed by NGS. Cellular kinetics were analyzed in peripheral blood samples by qPCR to detect the liso-cel transgene. Correlative analysis studies of baseline markers of tumor burden (sum of the product of diameters; CD19⁺ cells/μL; percent CLL cells in bone marrow biopsies or aspirates) with liso-cel expansion were evaluated by MRD status. Statistical analyses were performed using the Wilcoxon signed-rank test.

Results: Of the 80 pts who were evaluable for peripheral blood MRD, 34 had a best overall response of SD, 19 of whom achieved uMRD and 15 who were MRD+. Greater liso-cel expansion parameters (median maximum expansion and area under the curve from 0–28 days postinfusion) were observed in all pts, including those with SD, who achieved uMRD versus MRD+ status (P < 0.0001), suggesting that higher liso-cel expansion after infusion was associated with achievement of uMRD independent of iwCLL 2018 response. Regardless of baseline tumor burden, pts with higher liso-cel expansion achieved uMRD after liso-cel treatment. A positive association between tumor burden and liso-cel expansion in pts with SD and uMRD was also observed. In contrast, pts with SD who were MRD+ had lower liso-cel expansion and trends of higher baseline disease burden. Liso-cel expansion in pts with SD and uMRD clustered with the responders, who all achieved uMRD status (in those evaluable for MRD). Notably, 4 pts with SD and uMRD had a durable disease control of > 22 months. We wanted to further understand the relationship between uMRD and durable disease control. Given that the median PFS of pts with SD and uMRD was 6 months, we evaluated the association between tumor burden and liso-cel expansion in pts who had a PFS of ≤ 6 months or > 6 months. Although no clear association was observed with liso-cel expansion and tumor burden within these 2 groups, 4 out of 5 pts with SD and uMRD with longer disease control (PFS > 6 months) had a > 98% decrease in sample-level MRD from Month 1 to Month 3. In contrast, in pts with SD and uMRD with PFS ≤ 6 months, 5 out of 7 pts had a > 70% increase in sample-level MRD from Month 1 to Month 3.

Conclusions: In this exploratory analysis of pts with R/R CLL who had SD by iwCLL 2018 criteria after liso-cel treatment, greater liso-cel expansion, regardless of baseline tumor burden, correlated with blood uMRD status. Additionally, those with a PFS > 6 months achieved deeper clearance of blood sample-level MRD within 3 months of treatment versus those with a PFS ≤ 6 months, suggesting that MRD kinetics may identify pts with SD who can achieve durable disease control despite not achieving a response per iwCLL 2018 criteria. Further investigation is needed to better understand which subsets of pts with CLL who had SD may derive clinical benefit from liso-cel.